The effects of chronic administration of nimodipine on age‐related changes in nitric changes in nitric oxide and its synthase in senescence‐accelerated mouse brain

Abstract

The levels of nitric oxide (NO) and NO synthase (NOS) activities in the brain of young‐adult (3 months old), aged (11 moths old) and nimodipine‐administered (11 months old) senescence‐accelerated mouse (SAM), of which SAMP8 sub‐strain is inferior in acquisition of learning and has a lower content in testosterone, were compared. Nimodipine, which is L‐type calcium ion channel blocker and has memory‐enhancing effects, was administered orally for 5 months. In the cerebral cortex of aged SAMP8, NOS activity was increased compared with that of young‐adult SAMP8. Though nimodipine did not alter the contents of NO in any brain regions compared with those in aged SAMP8, nimodipine increased NOS activity in the aged cerebellum. Our data suggest that nimodipine may increase NOS activity through elevation of testosterone level, as testosterone increases NOS only in the cerebellum, although further work is clearly needed to ascertain effects of nimodipine on testosterone metabolism and maintenance in the acquisition of learning.

Phosphodiesterase inhibition by sildenafil citrate attenuates a maze learning impairment in rats induced by nitric oxide synthase inhibition

“…In conclusion, there is growing literature linking the effects of age and age-related cognitive decline with changes in NO and NOS activity (Arnaiz et al 2004;Cha et al 1998;Chalimoniuk and Strosznajder 1998;de la Torre et al 2003;Dere et al 2002;Inada et al 1996Inada et al , 1997Kuo et al 1997;Law et al 2003;Liu et al 2004;Noda et al 1997;Reddy and Kulkarni 1998;Strolin Benedetti et al 1993;Yamada et al 1996). In the present study, downstream upregulation of the NO-cGMP pathway with the PDE5 inhibitor sildenafil citrate attenuated the complex maze impairment produced by NOS inhibition, a model of agerelated cognitive decline (Ingram et al 1994a(Ingram et al ,b, 1996Meyer et al 1998a).…”

Site‐specific DNA damage at GGG sequence by oxidative stress may accelerate telomere shortening

“…Activated inflammatory cells such as phagocytes produce O 2 − and NO through the induction of nitric oxide synthase (NOS). In the cerebral cortex of the aged senescence‐accelerated mouse (SAM), of which the SAMP8 sub‐strain is inferior in acquisition of learning, NOS activity was increased compared with that of young SAMP8 [48]. The present results show that NO plus O 2 − efficiently cause base alteration at the 5′ site of 5′‐GGG‐3′ in the telomere sequence in the DNA fragment (5′‐(TAGTAG) 4 (TTAGGG) 4 ‐3′).…”

Calcium Channel Blockade Enhances Nitric Oxide Synthase Expression by Cultured Endothelial Cells

“…[2][3][4][5] However, it is not clear whether the given calcium channel blockers enhance the activity or production of NOS. In …”

“…This observation can account for the reported improvement in endothelial function with chronic administration of several different calcium channel blockers in animals with hypertension and chronic renal failure. [2][3][4][5] It is important to note that the addition of felodipine in the given concentrations did not affect 10% FCS-stimulated endothelial cell growth as determined by DNA synthesis and cell count in vitro. This finding contrasted the growth inhibitory effect of calcium channel blockade on the rat mesangial cells shown in this study and by other investigators.…”

“…2 In addition, administration of the calcium channel blocker nicardipine has been shown to reverse the age-dependent decline in brain NOS activity and NO production in the senescent mouse. 3 Likewise, chronic administration of the calcium channel blocker RO-5967 mitigated hypertension, reduced intimal inflammatory infiltrate, and improved acetylcholine-induced vasorelaxation of aortic rings in spontaneously hypertensive rats. 4 In a recent study we demonstrated a marked reduction of NO production together with depressed vascular and remnant kidney NOS activity, as well as endothelial and inducible NOS (eNOS and iNOS) protein abundance, in rats with chronic renal failure.…”